Multi-layer biodegradable device having adjustable drug release profile

ABSTRACT

Methods and apparatus for a biodegradable multi-layer device suitable for medical applications are provided, wherein the device is formed from multiple film-layers configured to have different characteristics from one another such as different release profiles for therapeutic agents, adhesive properties, stiffness properties, and solubility properties. The film-layers may include a solid fibrinogen component. A device having multiple film-layers may take a non-adherent form during delivery to a target location within or on tissue, and thereafter may be exposed to moisture to take an adherent form on the tissue. The device may include a number of additives, including materials to improve the mechanical properties of the device, or one or more therapeutic or contrast agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional patent application of U.S. patentapplication Ser. No. 13/794,355, filed Mar. 11, 2013, now U.S. Pat. No.9,271,925, the entire contents of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates generally to devices for drug delivery,including free-standing multi-layer biodegradable devices, especiallyuseful in promoting healing of iatrogenic wounds and reducing theformation of post-operative lesions.

BACKGROUND OF THE INVENTION

Wounds to the human anatomy may result from interventional,minimally-invasive and/or intraoperative surgical procedures, acts,diseases, and/or underlying conditions. For example, iatrogenic woundsgenerally are formed during surgery for treating sinusitis, and due tothe complicated topology of the sinuses, may take extended periods toheal. In addition, certain portions of the human anatomy are prone tothe development of post-operative lesions, which often require treatmentvia subsequent surgical intervention.

Sinusitis is inflammation of the paranasal sinuses generally due toinfection, allergies, or autoimmune issues. Chronic sinusitis affectspersons of all age groups and is one of the more prevalent chronicdiseases in the United States, affecting 37 million Americans. Chronicsinusitis may persist for 12 weeks or longer. Surgery, althoughminimally invasive, is generally reserved for acute/intermittentrhinosinusitis and chronic/persistent rhinosinusitis unresponsive toconservative medical treatment or where there are complicationsassociated with those conditions. Functional endoscopic sinus surgery(FESS) of the diseased sinus mucosa has been proposed to enableventilation through the natural ostia and restore mucociliary clearanceusing a minimally invasive endoscopic technique. Although FESS hasproven to be an effective procedure in treating chronic sinusitis, theoutcome of the surgery can become significantly complicated by operativepathologies, including delayed wound healing, stenosis of the sinuspassageways (˜ in 20-30% of cases), adhesions, and the formation ofpolyps. Various mechanical means such as nasal stents and packings havebeen developed to treat such wounds; however, experience has shown thatthese methods do not provide an effective way of addressing thecomplications.

Pharmaceutical treatment of iatrogenic wounds with therapeutic agentssuch as steroids has been shown to reduce postoperative complications.However, there does not exist in the prior art an effective manner fordelivering appropriate dosages of therapeutic agents over a desiredtimeframe within the sinus cavities.

Balloon sinus dilation is a relatively new technique for treatingchronic sinusitis by opening blocked passages with balloon inflation.While more limited in application than FESS, this modality may becomethe treatment of choice for limited or moderate sinus disease.Accordingly, it would be desirable to provide an effective device fordelivering a therapeutic agent to sinus tissue over a period of timefollowing balloon sinus dilation.

U.S. Patent Application Publication Nos. 2011/0071498 and 2011/0071499to Hakimimehr, assigned to the assignee of the present invention, thecontents of both of which are hereby incorporated by reference, describedevices having a free-standing film of solid fibrinogen, and optionallysolid thrombin, configured in the form a thin sheet. The device may beconfigured to release a therapeutic agent over time.

It would be desirable to provide a device, such as described in theforegoing Hakimimehr publications, that permits the release of differenttherapeutic agents over the same temporal profiles and/or differenttherapeutic agents over different temporal profiles.

SUMMARY OF THE INVENTION

In view of the foregoing, the present invention is directed to methodsand apparatus for providing a biodegradable multi-layer device suitablefor medical applications, especially treating, supporting, protecting orjoining weakened tissue or vessels, and for promoting healing of same,resulting from iatrogenic causes, disease or underlying conditions.Advantageously, the multi-layer device of the present invention isformed from multiple film-layers having different characteristics fromone another, e.g., configured to release the same or differenttherapeutic agents at the same or different release times, differentadhesive properties, different stiffness properties, and/or differentsolubility properties.

In accordance with one aspect of the present invention, a device isprovided comprising a first film-layer and a second film-layer bonded tothe first film-layer. The first film-layer includes solid fibrinogen andis formed by processing (e.g., drying) a first composition for a firsttime interval to produce a first characteristic of the first film-layer.The second film-layer includes solid fibrinogen and is formed byprocessing (e.g., drying) a second composition for a second timeinterval to produce a second characteristic of the second film-layer.Preferably, the second characteristic is different than the firstcharacteristic. As will be appreciated by one of ordinary skill in theart, while the device described herein is generally described as havingtwo film-layers, a device constructed in accordance with the principlesof the present invention may include any number of film-layers formedfrom multiple different compositions.

The first film-layer further may include a first therapeutic agent andthe second film-layer further may include a second therapeutic agentwhich may be the same or different type or quantity as the firsttherapeutic agent. When the film-layers include a therapeutic agent, thefirst characteristic may be a first release profile for the firsttherapeutic agent and the second characteristic may be a second releaseprofile for the second therapeutic agent. The first therapeutic agent orthe second therapeutic agent or both may comprise one or moreanti-inflammatory agents, anti-allergenic agents, anti-bacterial agents,anti-viral agents, anticholinergic agents, antihistamines,antithrombotic agents, anti-scarring agents, antiproliferative agents,antihypertensive agents, anti-restenosis agents, healing promotingagents, vitamins, proteins, genes, growth factors, cells, RNA, or DNA.

In accordance with some aspects of the present invention, the firstcharacteristic may be a first adhesive property of the first film-layer,a first solubility property of the first film-layer, a first surfaceroughness or texture property of the first film-layer, and/or a firststiffness property of the first film-layer. The second characteristicmay be a second adhesive property of the second film-layer, a secondsolubility property of the second film-layer, a second surface roughnessor texture property of the second film-layer, and/or a second stiffnessproperty of the second film-layer. Advantageously, such first propertiesmay be different from such second properties.

The first surface roughness or texture property of the first film-layermay include surface projections, perforations, microstructures,nanostructures, ridges, dimples, or any combination thereof and thesecond surface roughness or texture property of the second film-layermay include surface projections, perforations, microstructures,nanostructures, ridges, dimples, or any combination thereof.

The device may be configured to form a fibrin patch upon exposure tomoisture (e.g., water, bodily fluids).

The first time interval for processing the first composition may bedifferent from the second time interval for processing the secondcomposition. In one embodiment, the first time interval is the amount oftime required to substantially eliminate a first amount of non-aqueoussolvent from the first composition and the second time interval is theamount of time required to substantially eliminate a second amount ofnon-aqueous solvent from the second composition. The first compositionmay be different than the second composition (e.g., different types ofmaterials and/or different quantities of materials). The firstcomposition may be bonded to the second composition before, during, orafter the first and second film-layers are formed.

The solid fibrinogen of the first film-layer or the second film-layer orboth may be prepared from unsalted fibrinogen. The first film-layer orthe second film-layer or both further may include calcium salt, solidthrombin mixed with the solid fibrinogen, a plasticizer, a contrastagent that renders the device radiopaque, or any combination thereof.

The first film-layer or the second film-layer or both may includesurface projections, perforations, microstructures, nanostructures,ridges, and/or dimples. The first film-layer or the second film-layer orboth may be coated with, disposed between, and/or sandwich a protectivelayer. The device also may include an intermediate layer disposedbetween the first film-layer and the second film-layer. The intermediatelayer may be configured to dissolve to create a reservoir, pores, void,or channel between the first film-layer and the second film-layer.

In accordance with one aspect of the present invention, a method ofmanufacturing a device is provided. The method includes forming a firstfilm-layer from a first composition comprising solid fibrinogen and afirst amount of non-aqueous solvent (e.g., ethanol) by processing (e.g.,drying) the first composition for a first time interval required tosubstantially eliminate the first amount of non-aqueous solvent. Themethod further includes bonding a second film-layer to the firstfilm-layer, wherein the second film-layer is formed from a secondcomposition comprising solid fibrinogen and a second amount ofnon-aqueous solvent (e.g., ethanol) by processing (e.g., drying) thesecond composition for a second time interval required to substantiallyeliminate the second amount of non-aqueous solvent. The first timeinterval may be different from the second time interval.

Bonding the second film-layer to the first film-layer may includebonding the second film-layer to the first film-layer using anintermediate layer disposed between the first film-layer and the secondfilm-layer. The intermediate layer may be configured to dissolve toleave a pore, a void, a reservoir, and/or a channel between the firstfilm-layer and the second film-layer. Bonding the second film-layer tothe first film-layer may occur before, during, or after forming thefirst film-layer and before, during, or after forming the secondfilm-layer. Bonding the second film-layer to the first film-layer mayinclude coupling the first film-layer to the second composition beforeforming the second film-layer. In addition, bonding the secondfilm-layer to the first film-layer may include mechanically, chemicallyor electrically depositing, spraying, or casting the second film-layeron the first film-layer.

The first composition may be substantially identical to the secondcomposition, except the first amount of non-aqueous solvent is differentfrom the second amount of non-aqueous solvent. The first film-layer andthe second film-layer have substantially identical opticalcharacteristics.

In accordance with yet another aspect of the present invention, a methodof delivering a device to a bodily tissue is provided. The methodincludes advancing a device comprising a first film-layer bonded to asecond film-layer to a target location and applying the device to thebodily tissue. The first film-layer includes solid fibrinogen and isformed by processing a first composition for a first time interval toproduce a first characteristic of the first film-layer. The secondfilm-layer includes solid fibrinogen and is formed by processing asecond composition for a second time interval to produce a secondcharacteristic of the second film-layer. The second characteristic maybe different than the first characteristic. The target location mayinclude, but is not limited to, hollow body organs such the esophagus,stomach, intestines, bronchus, trachea, carina of the trachea, lung,larynx, urethra, ureter, the sinus, the ear, eye, or the heart; alamina; vasculature such as a vessel; wound; tumor; or bone such as aspine

Advancing the device may include advancing the device using a deliverysystem. Applying the device may include expanding an expandable memberof the delivery system. The delivery system may have a protective sheathor protective outer or inner layer to prevent premature device placementor to prevent premature exposure of the first and second film layers tomoisture before the device is applied to the bodily tissue. The devicemay be temporarily attached to the delivery system and may be releasablefrom the delivery system. The delivery system may be configured toconform the device to a three-dimensional shape and/or to the bodilytissue while applying the device to the bodily tissue. A component maybe delivered to the device after application to the bodily tissue suchthat the component augments the device function by supplying the devicewith an activating agent or therapeutic agent. The device may also beapplied to the bodily tissue using a trocar, tweezers, forceps, and/orclamps.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a first illustrative embodiment of adevice of the present invention.

FIGS. 2A through 2C are schematic views of an alternative illustrativeembodiment of a device of the present invention having an intermediatelayer disposed between the first and second film-layers, wherein theintermediate layer is sandwiched between the film-layers in FIG. 2A, theintermediate layer is encased in the first and second film-layers inFIG. 2B, and FIG. 2C is a cross-sectional view of FIG. 2B.

FIGS. 3A through 3C are schematic views of alternative illustrativeembodiments of a device of the present invention in which twofilm-layers are sandwiched between protective layers in FIG. 3A, aresandwiched between perforated layers in FIG. 3B, or are coated withpowder in FIG. 3C.

FIG. 4 is a schematic view of another alternative illustrativeembodiment of a device of the present invention wherein discretesegments of solid fibrinogen components are embedded in a water-solubleprotective layer.

FIGS. 5A-5D are, respectively, a schematic view of a further alternativeembodiment of the device of present invention wherein discrete films ofat least solid fibrinogen components are arranged on a protective layer,and illustrative views showing application of the device of FIG. 5A to atarget location.

FIGS. 6A-6E are illustrative configurations for articles formed inaccordance with the present invention.

FIGS. 7A and 7B illustrate one method by which a device of the presentinvention may be affixed to a balloon catheter.

FIGS. 8A and 8B illustrate an alternative balloon catheter that may beused to deliver the device of the present invention.

FIGS. 9A-9E illustrate a method of deploying the device of the presentinvention on bodily tissue.

FIG. 10 is a graph showing the percentage of drug release from exemplaryfilm-layers as a function of time.

FIG. 11 is a graph showing the force by extension of exemplaryfilm-layers for analyzing adhesive properties.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is generally directed to a multi-layerbiodegradable device for use in medical procedures for treating,healing, supporting, protecting or joining weakened or wounded tissue orvessels, resulting from interventional, minimally-invasive andintraoperative surgical procedures, disease, and/or underlyingconditions. The multi-layer device of the present invention also may beused for isolating, occluding, supporting, and/or treating tissue, forexample, as a drug delivery vehicle in the sinuses.

In accordance with one aspect of the invention, the multi-layer devicemay incorporate therapeutic agents such as drugs, genes or otherbioactive agents that are eluted into the surrounding tissue to providelocalized treatment or into an adjacent bloodstream to provide systemictreatment. Alternatively, such drugs, genes or other bioactive agentsmay be released into surrounding tissue or an adjacent bloodstream asthe device biodegrades. Advantageously, the multi-layer device of thepresent invention is configured like the biodegradable devices of theaforementioned Hakimimehr applications with an improved multi-layerconfiguration whereby film-layers are formed with differentcharacteristics, for example, to release different therapeutic agents atdifferent release times or attain finer control of the therapeutic agentdelivery rate.

The multi-layer device of the present invention also may include visibledyes or radiopaque materials to enhance visibility and placement of thedevice during deployment.

The multi-layer devices described herein may be delivered to a portionof the body using one or more delivery systems having one or moreexpandable members (e.g., an expandable cage, a balloon, and the like)and/or using a trocar, tweezers, forceps, clamps, or the like.

Multi-Layer Device Configurations

Multi-layer devices constructed in accordance with the principles of thepresent invention may be manufactured in either an adherent ornon-adherent state. A multi-layer device also may be manufactured in anon-adherent state, and activated prior to use, for example, by dippingin warm water prior to application or delivery to the body. As yetanother alternative, the multi-layer device may include a water-solubleprotective coating, for example, for intravascular applications, toprevent the fibrin polymerization process from beginning before thedevice is delivered to a target location.

Referring now to FIG. 1, a first embodiment of a multi-layer deviceconstructed in accordance with the principles of the present inventionis described. Device 100 comprises first film-layer 102, which may befree-standing, having unreacted fibrinogen 104, and second film-layer106, which may be free-standing, bonded to first film-layer 102, andhaving unreacted fibrinogen 104. First film-layer 102 and secondfilm-layer 106 may include one or more additional components or agents,such as therapeutic agents, unreacted thrombin, calcium salt, FactorXIII, aprotinin, and/or other additives (e.g., plasticizers,stabilizers, dyes, radio-opacifiers, film-forming agents, and the like).Preferably, first film-layer 102 is processed in a manner to produce afirst characteristic of first film-layer 102 and second film-layer 106is processed in a manner to produce a second characteristic of secondfilm-layer 106 different than the first characteristic. Examples of suchcharacteristics include release profiles of therapeutic agents, adhesiveproperties, stiffness properties, and solubility properties.

First film-layer 102 may be formed from a first composition of materialsthat may include fibrinogen, thrombin, non-aqueous solvent(s),therapeutic agent(s), calcium salt, Factor XIII, aprotinin, and/or otheradditives (e.g., plasticizers, stabilizers, dyes, radio-opacifiers,film-forming agents, and the like). The first composition may be pouredin a mold and processed for a first time interval, for example, the timerequired to substantially eliminate the amount of non-aqueous solvent inthe first composition. The composition may be processed by, for example,drying including freeze-drying and vacuum-drying or incubating thecomposition. The first time interval may be predetermined by, forexample, a technician or a computer or may be determined during a dryingprocess by the technician using a computer that monitors the process orsolely by the computer. The computer may be coupled to suitable sensorsfor determining when the amount of non-aqueous solvent is substantiallyeliminated. As will be readily understood by one of ordinary skill inthe art, the term substantially as used herein means considerably oramply, e.g., greater than 50%, greater than 60%, greater than 70%,greater than 80%, greater than 90%, greater than 95%, greater than 99%.

Second film-layer 106 may be formed from a second composition ofmaterials that may include fibrinogen, thrombin, non-aqueous solvent(s),therapeutic agent(s), calcium salt, Factor XIII, aprotinin, and/or otheradditives (e.g., plasticizers, stabilizers, dyes, radio-opacifiers,film-forming agents, and the like). The second composition may be thesame as the first composition or may be different from the firstcomposition e.g., different ratios of thrombin to fibrinogen, ordifferent amounts of plasticizer, as required for a particularapplication such that the film-layers have different setting ordegradation times, different stiffness, and/or release different drugs.The second composition may be poured in a mold and processed for asecond time interval different from the first time interval, forexample, the time required to substantially eliminate the amount ofnon-aqueous solvent in the second composition. This composition also maybe processed by, for example, drying including freeze-drying andvacuum-drying or incubating the composition. This second time intervalmay be predetermined or determined during a drying process in the mannerdescribed above with respect to the first time interval.

The amount of time required to substantially eliminate the amount ofnon-aqueous solvent in a composition may be varied by varying the amountof non-aqueous solvent in the composition. Applicants have discoveredthat the amount of non-aqueous solvent in each composition has asignificant impact on the characteristics (e.g., therapeutic releaseproperties, adhesive properties, stiffness properties, solubilityproperties) of the film-layer that is formed from each respectivecomposition. Applicants have further discovered that varying the amountof time required to substantially eliminate the amount of non-aqueoussolvent by, for example, varying the air flow rates and/or humidity inthe drying environment for each composition will also impact thecharacteristics of the film-layer that is formed from each respectivecomposition.

In one embodiment, the time required to substantially eliminate theamount of non-aqueous solvent is varied by varying the humidity fordifferent film-layers in a device that includes three film-layers. Themiddle film-layer of a multi-layer construct is configured fortherapeutic agent delivery and is dried slowly in high humidity whilethe two outer films are dried significantly faster in lower humidity. Inthis embodiment, for example, the middle film-layer has a fibrinogen tonon-aqueous solvent ratio of 1:100 (wt:wt) to 1:200 and is processed inan ambient humidity of 50-70%. The outer films have substantially lowerfibrinogen to non-aqueous solvent ratio of less than 1:100 for example1:40 and are processed in an ambient humidity of 10-50% or for example20-40%. As a result, the middle film-layer of the device has differentcharacteristic than the outer film-layers.

First film-layer 102 may include a first therapeutic agent while secondfilm-layer 106 may include a second therapeutic agent which may be thesame or a different type of therapeutic agent as the first therapeuticagent and may be provided in the same or different amount as the firsttherapeutic agent. Advantageously, first film-layer 102 has a firstrelease profile, e.g., configured to release the first therapeutic agentover a first period of time, and second film-layer 106 has a secondrelease profile, e.g., configured to release the second therapeuticagent over a second period of time, that may be different from the firstrelease profile. The therapeutic agent release profile for eachfilm-layer is directly impacted by the method of forming eachfilm-layer.

Preferably, first film-layer 102 is bonded to second film-layer 106 andthe bonding may occur before or after the film-layers are formed. Forexample, bonding first film-layer 102 to second-film layer 106 mayinclude: (a) separately forming first film-layer 102 and secondfilm-layer 106 and then bonding first film-layer 102 to secondfilm-layer 106; (b) bonding first composition to second compositionbefore first and second film-layers 102 and 106 are formed; (c) bondingfirst composition to second film-layer 106 before first film-layer 102is formed; or (d) bonding second composition to first film-layer 102before second film-layer 106 is formed. First film-layer 102 may bebonded to second film-layer 106 using one or more suitable biocompatibleadhesives, a non-aqueous solvent such as ethanol, by pressing thefilm-layers together, or by painting, brushing, casting, or spraying onefilm-layer on another film-layer.

Device 100 may be configured to form a patch upon exposure to moisture.First film-layer 102 and second film-layer 106 include unreacted (e.g.,solid) fibrinogen and optionally unreacted (e.g., solid) thrombin thatmay be polymerized to form a patch only after being exposed to moisture(e.g., water, bodily fluids such as blood, lymph, and mucous, and thelike), preferably at the target location. When combined in a moistenvironment, thrombin converts fibrinogen into fibrin monomers, whichare in turn polymerized to form fibers. These fibrin fibers jointogether into a network structure, resulting in a fibrin matrix. In anembodiment where the device does not include thrombin, device 100 mayform a fibrin patch when fibrinogen in the film-layers reacts withnaturally occurring thrombin in bodily fluids. The patch of the presentinvention may include one or more additional components, such ascalcium, Factor XIII and bovine aprotinin, which may affect the rates ofpolymerization and biodegradation. Importantly, because fibrin is a partof the body's natural clotting mechanism, the in situ formed fibrinpatches of the present invention are biocompatible, non-thrombogenic,biodegradable, and have a high affinity for various biological surfaces.In addition, because, in accordance with the present invention, thefibrinogen and thrombin may be combined in a non-aqueous environment,the components of the device do not polymerize to form a patch, e.g., afibrin patch, until the device is exposed to an aqueous environment,such as bodily fluids.

As the polymerization process begins (e.g., when thrombin and fibrinogenare combined in the presence of moisture), the patch may temporarilybecome a gel and become highly adherent. Generally, it is expected thatthe patch may be freely manipulated, stretched, or deformed when in itstemporary gel form. The duration of the gel stage may be dependent onthe relative and overall concentrations of the fibrinogen and thrombincomponents, as well as the presence of any other components.

FIGS. 2A-2C illustrate an aspect the present invention, in which thedevice comprises an intermediate layer disposed between the film-layers.In FIG. 2A, device 200 comprises first film-layer 202, intermediatelayer 204, and second film-layer 206. First and second film-layers 202and 206 are similar to first and second film-layers 102 and 106,respectively, as described with respect to FIG. 1, and thus detaileddescriptions thereof are omitted for clarity and conciseness.Illustratively, intermediate layer 204 is sandwiched between firstfilm-layer 202 and second film-layer 206. In FIGS. 2B and 2C, device 210comprises first film-layer 212, intermediate layer 214, and secondfilm-layer 216. First and second film-layers 212 and 216 are similar tofirst and second film-layers 102 and 106, respectively, as describedwith respect to FIG. 1, and thus detailed descriptions thereof areomitted for clarity and conciseness. Illustratively, intermediate layer214 is encased in first film-layer 202 and second film-layer 206.

Intermediate layer 204, 214 may be an adhesive configured to bond firstfilm-layer 202, 212 to second film-layer 206, 216 and/or may comprise awater-soluble material, a material that is soluble in another media, amaterial that is electrolytically decomposable, a bioerodable orbiodegradable material, e.g., biodegradable polymer, combinationsthereof, or the like. Intermediate layer 204, 214 may be a continuouslayer, a perforated layer, discrete formations, powder formations, orthe like. In one embodiment, intermediate layer 204, 214 is configuredto dissolve upon exposure to moisture to leave a pore(s), a void(s), areservoir(s), and/or a channel(s) between first-film layer 202, 212 andsecond film-layer 206, 216. Such pore(s), a void(s), a reservoir(s), ora channel(s) permit fluid access within device 200, 210 and betweenfirst-film layer 202, 212 and second film-layer 206, 216. Such pore(s),a void(s), a reservoir(s), or a channel(s) also may act as actuatorsconfigured to collapse, swell, or otherwise mechanically change shape,to control mechanical aspects of device 200, 210 such as degradationrate or overall form factor or conformation of device 200, 210 and toallow for rapid release of therapeutic agent.

As will be readily apparent to one of ordinary skill in the art, firstfilm-layer 202, 212, second film-layer 206, 216, and/or intermediatefilm layer 204, 214 may be separated by, disposed between, coupled to,and/or encased in a protective layer(s) such as the protective layerdescribed below.

In FIG. 3A, device 300 is provided including first film-layer 302,protective layers 304, and second film-layer 306. First and secondfilm-layers 302 and 306 are similar to first and second film-layers 102and 106, respectively, as described with respect to FIG. 1, and thusdetailed descriptions thereof are omitted for clarity and conciseness.Protective layer 304 may at least temporarily protect the film-layersfrom certain substances or stimuli prior to or during delivery, forexample, exposure to moisture, to prevent premature activation.Alternatively, the protective layer may be selectively removed tocontrol the activation of the device. In embodiments in which the deviceis already in an adherent form, a protective layer may help preventpremature adhesion between the device and surrounding tissue. In otherinstances, the protective layer may protect the device from mechanicaldamage prior to or during delivery. In still other embodiments, aprotective layer may allow a device to be folded or otherwisemanipulated (cut, rolled, bent, etc.) without adhering to itself. In yetother embodiments, a protective layer may be used to at leasttemporarily join a device to a delivery system, as described below.

In some embodiments, the protective layer may be removed from the deviceprior to or during delivery of the device. In this way, a device may beconfigured such that only the fibrin-forming layers (as well as anadditives or therapeutic agents) are delivered to tissue. The protectivelayer may be made from a water-soluble material, a material that issoluble in another media, a material that is electrolyticallydecomposable, a bioerodable or biodegradable material, e.g.,biodegradable polymer, combinations thereof, or the like. Examples ofsuitable water-soluble materials include, but are not limited to,polysaccharides (e.g., hyaluronic acid, cellulose, hydroxypropylmethylcellulose, gelatin, starches, dextrans, alginates, their derivatives,and the like), contrast agents (e.g., diatrizoate, metrizoate,ioxaglate, iopamidol, iohexol, ioxilan, iopromide, iodixanol, and thelike), sugar-based polymers (e.g., sucrose, dextrose), water-solublehydrogels (polyethylene glycol, polyethylene oxide), combinationsthereof, and the like.

While device 300 is depicted in FIG. 3A as having protective layers 304on the outsides of film-layers 302 and 306, the device may include onlyone protective layer 304 attached thereto or a third protective layerbetween film-layers 302 and 306. Device 300 may also include aprotective layer that encases, e.g., covers all of the exposed surfacesof, film-layers 302 and 306. As will be appreciated by one of ordinaryskill in the art, while the device in this disclosure is generallydescribed as having two film-layers, the device may include one, two,three, four, five, or more film-layers and may have one, two, three,four, five or more protective and/or intermediate layers withoutdeparting from the scope of this invention.

In FIG. 3B, device 310 is described that includes first film-layer 312,perforated layers 314, and second film-layer 316. First and secondfilm-layers 312 and 316 are similar to first and second film-layers 102and 106, respectively, as described with respect to FIG. 1, and thusdetailed descriptions thereof are omitted for clarity and conciseness.Perforated layers 314 include a plurality of apertures 318 such thatperforated layers 314 and first and second film-layers 312 and 316 maybe exposed to moisture substantially simultaneously. Perforated layers314 may be configured similar to intermediate layer 204, 214, protectivelayer 304, or may be formed from a composition of materials such asfibrinogen, thrombin, non-aqueous solvent(s), therapeutic agent(s),calcium salt, Factor XIII, aprotinin, and/or other additives (e.g.,plasticizers, radio-opacifiers, film-forming agents, and the like).

In FIG. 3C, device 320 is described that includes first film-layer 322,powder formations 324, and second film-layer 326. First and secondfilm-layers 322 and 326 are similar to first and second film-layers 102and 106, respectively, as described with respect to FIG. 1, and thusdetailed descriptions thereof are omitted for clarity and conciseness.Powder formations 324 are powder and are coupled to the film-layersusing a suitable technique such as spray coating. Powder formations 324need not fully cover first and second film-layers 312 and 316 such thatthe film-layers and the powder may be exposed to moisture substantiallysimultaneously. Powder formations 324 may be configured similar tointermediate layer 204, 214, protective layer 304, or may be formed froma composition of materials such as fibrinogen, thrombin, non-aqueoussolvent(s), therapeutic agent(s), calcium salt, Factor XIII, aprotinin,and/or other additives (e.g., plasticizers, radio-opacifiers,film-forming agents, and the like). Preferably, powder formations 324comprise solid fibrinogen or a powder mixture of solid fibrinogen andsolid thrombin.

Referring to FIG. 4, a further alternative of a device constructed inaccordance with the principles of the invention is described. Device 400comprises discrete or interconnected portions or strands 402 and 406 ofsolid unreacted fibrinogen disposed within matrix 404. Matrix 404 may beconfigured similar to intermediate layer 204, 214, protective layer 304,or may be formed from a composition of materials such as fibrinogen,thrombin, non-aqueous solvent(s), therapeutic agent(s), calcium salt,Factor XIII, aprotinin, and/or other additives (e.g., plasticizers,radio-opacifiers, film-forming agents, and the like). In some of thesevariations, matrix 404 may protect components 402 and 406 from prematureactivation. Additionally, matrix 404 may provide device 400 withadditional flexibility or rigidity, as may be desired for a particularapplication. In one embodiment, component 402 is formed in a mannersimilar to first film-layer 102 of FIG. 1 and fibrin-forming component406 is formed in a manner similar to second film-layer 106 of FIG. 1such that components 402 and 406 have at least one differentcharacteristic from one another.

In one embodiment, components 402 and 406 include a mixture of unreactedfibrinogen and unreacted thrombin. In this embodiment, when device 400is delivered, e.g., into a sinus of a patient, the solid unreactedfibrinogen and thrombin portions 402 and 406 may adhere to tissue.However, matrix 404, which may be a water-soluble material, initiallyprotects the fibrin-forming components from polymerizing. Aswater-soluble matrix 404 dissolves during exposure within the body,portions 402 and 406 are exposed, thereby initiating polymerization.Such exposure also may allow the device to form fibrin gel to adhere tothe bodily tissue and cure to form a fibrin-matrix patch. Pressureapplied by a delivery device (e.g., by an inflated balloon), may causeportions 402 and 406 to join and form a continuous film-layer within thebody. In other embodiments, matrix 404 may be a biodegradable material,such that exposed portions of the unreacted fibrin-forming components402 and 406 become adherent, thereby allowing device 400, includingbiodegradable matrix 404, to form a patch(es) and adhere to surroundingtissue.

In other variations, a multi-layer device of the present invention maybe formed with the unreacted fibrinogen arranged in predeterminedpatterns. For example, in some variations, the components, e.g.,film-layers, may be arranged in a mesh-like pattern. In still othervariations, the components may be divided into a plurality of discretesegments. FIGS. 5A-5D illustrate one such variation, device 500. FIG. 5Ais a perspective view of device 500, which includes film-layers 504(similar to first film-layer 102 of FIG. 1) and film-layers 516 (similarto second film-layer 106 of FIG. 1) deposited on protective layer 502(similar to protective layer 304 of FIG. 3A). While shown in FIG. 5A ashaving protective layer 502, it should be appreciated that film-layers504 and 516 alternatively may be deposited directly onto one or moreportions of a delivery device, with or without a protective layer. Anadditional protective layer(s) (not shown) may be used to cover some orall of the film-layers during delivery.

As illustrated in FIGS. 5B through 5D, although film-layers 504 and 516may be divided into a number of discrete segments, some or all of thefilm-layers 504 and 516 may be joined in situ to form a continuous film.More specifically, in embodiments in which film-layers 504 and 516 takeon a gel form after activation, the segments may be manipulated orremodeled by the application of one or more forces. For example, whendevice 500 described above is pressed against sinus wall 506 by anexpandable delivery device (not shown), the device and sinus wall mayapply pressure (indicated by the arrows in FIG. 5B) to film-layers 504and 516 that cause the gelatinous, partially-cured film-layers 504 and516 to deform outwardly, as shown by arrows 510. This deformation may inturn cause individual film-layers 504 and 516 to join into solid film512, as depicted in FIG. 5C. Protective layer 502 may thereafter beremoved or dissolve, as shown in FIG. 5D.

Dividing the unreacted fibrinogen components into discrete film-layers504 and 516 may provide a number of advantages. For example, a devicemade up of discrete film-layers 504 and 516 may have additionalflexibility compared to a solid continuous layer, thereby enabling thedevice to be folded to facilitate transluminal delivery. In otherinstances, discrete film-layers 504 and 516 may be used to form acontinuous film that will not block a side branch when deployed in abranched blood vessel. In such cases, it is expected that only thosefilm-layers 504 and 516 that contact a tissue surface will deform, andthus film-layers 504 and 516 that do not contact tissue will notcontribute to forming a continuous film. As such, if a balloon carryingdiscrete film-layers 504 and 516 is expanded inside of a branchedvessel; those segments that are expanded toward the side branch will notcontact tissue.

A multi-layer device of the present invention may have any suitable sizeand shape, such that the dimensions of the device may be determined atleast in part by the dimensions of the anatomy in which the device willbe applied. In addition, devices of unreacted fibrinogen or thrombin,with or without additional additives as described above, may be modeledinto any suitable size of shape, depending upon the intendedapplication. FIGS. 6A-6E illustrate a number of devices with multiplefilm-layers and articles modeled from such devices. For example, FIG. 6Aillustrates device 600 having the form of a hollow cylinder, and mayfind particular utility where the device will be placed in a cylindricalhollow body organ. Device 602 of FIG. B illustrates that a device of thepresent invention may take on any other three-dimensional shape, such asa frustroconical section.

Other suitable three-dimensional shapes may include, but are not limitedto, spheres, hemispheres and cones. In FIG. 6C, device 604 is configuredas a branched cylinder having main trunk 606 and first 608 and second610 side branches, such as may be required to provide internal orexternal support for a branched vessel. While shown in FIG. 6C as havinga generally y-shaped configuration, device 604 may be configured suchthat side branches 608 and 610 project from main trunk 606 at anydesired point along the length of main trunk 606.

In other embodiments, a device constructed in accordance with theprinciples of the present invention may be formed in a flat shape, suchas device 612 of FIG. 6D. While shown in FIG. 6D as being approximatelyrectangular in shape, device 612 may be any suitable shape, including,but not limited to, a circle, an oval, a triangle, a square, anotherpolygon, or a shape with irregular geometry. Additionally, device 612may be rolled, folded, bent or otherwise modified to form athree-dimensional shape. For example, FIG. 6E shows rectangular device614 that has been curved to form a half-cylinder, e.g., to mate with aninterior surface of a vessel to occlude or isolate an aneurysm. In othervariations, the shape of the device may be dependent on the system thatwill deliver it. For example, a device, according to the presentinvention, may be formed by depositing a film-layer of unreactedfibrinogen and thrombin, or just unreacted fibrinogen, with or without asalt component, on a portion of the delivery system (e.g., a balloon).In such instances, the shape of the device will be the same or similarto the shape of delivery system.

It should be appreciated that the shape and dimensions of a device maychange before or during delivery of the device and before or afterformation of the patch. For example, the device may be folded, crimped,stretched or otherwise deformed in a manner that modifies, temporarilyor permanently, the shape of the device. Furthermore, the ultimate sizeand shape of the in situ device formed within the body may differ fromthe shape of the device as manufactured. Due to the deformability of thefibrinogen and thrombin components during polymerization, some devicesmay be molded or otherwise deformed during delivery. For example, invariations where a cylindrical device is delivered using a balloon,inflation of the balloon may cause the device to expand to a largerradius.

The device may also incorporate specific features to allow foraccelerated tissue healing or improved therapeutic benefit. Featuressuch as perforations in a single layer or through the device and throughall layers may allow for more rapid tissue in growth or discreteexposure of underlying layers within the device to the tissue surface.The device also may include specific surface architectures or structuressuch as projections, ridges, dimples, or micro or nanostructures thatenhance bonding and/or improve penetration of therapeutic agents intothe tissue. Such surface architectures or structures may be on theentire device, or on individual or multiple layers including afilm-layer, an intermediate layer, and/or a protective layer.

Delivery Systems and Methods

The multi-layer devices described herein may be delivered using of anumber of previously-known delivery systems, which may comprise, forexample, one or more expandable members, such as a balloon or expandingmandrel or cage. In embodiments that include an expandable member, theexpandable member may be expanded at the delivery site to position adevice so that it is in apposition with tissue and to expose the deviceto moisture at the tissue, to optionally form a patch. In instanceswhere a device is placed in a dry environment, or when the deliverysystem is used to deliver a liquid component, the delivery system mayadditionally include one or more lines, lumens, ports or the like fordelivering water or a liquid component to the device to expose thedevice to moisture.

As explained above, the multi-layer devices may be configured to containpore(s), a void(s), a reservoir(s), and/or a channel(s), e.g., afterdissolution of an intermediate layer. In one embodiment, such pore(s), avoid(s), a reservoir(s), and/or a channel(s) may be expanded and/oraccessed by the delivery system. In such an embodiment, the deliverysystem includes a needle(s), line(s), lumen(s), and/or port(s)configured to deliver a fluid, therapeutic agent, and/or activatingagent to the pore(s), a void(s), a reservoir(s), and/or a channel(s)after in vivo implantation of the device.

In instances where the device is delivered using a balloon catheter, theballoon may be compliant, semi-compliant, or non-compliant. When aballoon catheter is used to deliver a multi-layer device of the presentinvention, the device may first be placed on or otherwise attached tothe balloon. In some variations, a device may be mechanically attachedto the balloon. Alternatively, one or more clips, sutures, magnets,coatings or other mechanical structures may be used to hold the deviceto the balloon. In variations where a non- or semi-compliant balloon iseither folded or rolled, the folding or rolling of the balloon may holdthe device against or to the balloon. FIGS. 7A and 7B illustrate onemanner by which a device may be folded with a non-compliant orsemi-compliant balloon to mechanically hold the device on the balloon.In particular, FIG. 7A depicts cylindrical device 700 (similar to device100 of FIG. 1) and balloon catheter 702 comprising balloon 704. As shownin FIG. 7A, balloon 704 has been placed inside of the device 700 andinflated. To hold device 700, balloon 704 may be deflated and folded.During this process, device 700 becomes folded along with thenon-compliant balloon, as shown in FIG. 7B, such that the resultingfolds of balloon 704 temporarily hold device 700 on the balloon. Device700 is released when balloon 704 is later re-inflated and may beactivated to form a patch upon exposure to moisture.

In other embodiments, the device may be temporarily attached to theballoon using one or more adhesives, which may be water-soluble andrelease the device when exposed to water. For example, in somevariations a water-soluble protective layer may be used to join a deviceto a delivery system and later release the device from the deliverysystem. In other variations, the adhesive may lose its grip on theballoon in response to one or more stimuli (e.g., chemical, electrical,thermal, optical, mechanical) which may be applied to the ballooncatheter to release the device in situ.

In still other embodiments, the unreacted fibrinogen and/or thrombincomponents of the device may be deposited directly onto the balloon of adelivery catheter using any suitable deposition process. Examples ofsuitable deposition methods include, but are not limited to, spraycoating, electrodepositing, dip coating, brushing, rolling, spinning,inkjet printing, casting or the like. Where the device comprisesmultiple layers (e.g., film-layers, protective layers, intermediatelayers, and adhesive layers), each layer may be applied sequentially,and may be applied using the same or different deposition methods. Forexample, a balloon may first be coated with a protective layer, a layerof unreacted fibrinogen and thrombin then applied, and finally theassembly may be coated with an additional protective layer, such as awater-soluble layer. When multiple discrete segments are used to createthe device, such as described with respect to device 500 of FIG. 5A,film-layers 504 and 516 may be applied simultaneously or sequentially.Additionally, the final layer of protective coating also may serve tosecure the device to the balloon.

When the fibrin-forming components are used to at least partially coat aballoon, the balloon may be either deflated or inflated when coated. Forexample, in some variations an inflated non-compliant or semicompliantballoon may be coated with a device, deflated, and then rolled or foldedwith the solid device attached thereto. In other instances, a deflatednon-compliant or semicompliant balloon may be rolled or folded, and thencoated with a device. Compliant balloons may be coated when they are atleast partially deflated. Additionally, the balloon of a ballooncatheter may be made from or coated with a non-adhesive material, suchas PTFE. In this case, the non-adhesive material may help to prevent thedevice from adhering to the balloon during delivery. The balloon of thedelivery catheter optionally may be textured, dimpled, or otherwisepatterned to allow for temporary mechanical adherence between theballoon and the device.

Referring now to FIGS. 8A and 8B, an alternative delivery systemsuitable for delivering a multi-layer device of the present invention isdescribed. Balloon catheter 800 includes curved, rectangular balloon 802that approximates a cylindrical shape when inflated. When deflated,balloon 802 may be folded or rolled into a spiral, as shown in a FIG.8B. Because balloon 802 may be laid flat when deflated, balloon catheter800 may find particular utility in instances where a device (not shown)is deposited directly on balloon 802, for example, by casting, sprayingor using an inkjet printing method. Additionally, because balloon 802approximates a cylindrical shape when inflated, blood may still passthrough lumen 804 defined by balloon 802 during deployment, therebyreducing the risk of upstream ischemia during placement of the deviceand optional activation of the patch.

Delivery systems suitable for delivering the multi-layer device of thepresent invention may additionally comprise one or more protectivesheaths. Generally, an expandable member may be placed in a low-profileconfiguration inside of a sheath, and advanced to a target site. At thetarget site, the sheath may be withdrawn (or the expandable memberadvanced) to reveal the expandable member. In this way, the sheath mayhelp to shield the device from exposure to moisture or other stimuli asthe device is advanced through the body. One such delivery system isdepicted in FIGS. 9A-9E. Alternatively, the sheath may have a diameterthat varies along the length of the catheter, e.g., having a smallerdiameter on the shaft and an enlarged diameter in the vicinity of theballoon, so that the sheath does not reduce flexibility of the deliverysystem.

In FIGS. 9A to 9E, delivery system 900 comprises sheath 902, collar 904disposed on sheath 902, and shaft 906 with cap 908. Cap 908 may beconfigured to engage the distal end of sheath 902 to seal the interiorof sheath 902 from the external environment during advancement of thedelivery system through a patient's anatomy. Shaft 906 may be slidablerelative to sheath 902 to move cap 908. To deliver a device withinbodily tissue BT, guidewire 912 is first advanced to a target site, asshown in FIG. 9B. Sheath 902 then is advanced along guidewire 912 viacollar 904, as depicted in FIG. 9C. While shown in FIGS. 9A-9E as havinga collar, delivery system 900 need not include such structure, butinstead may employ any other structure used for advancing a catheter.Once sheath 902 has been advanced to the target site, shaft 906 isadvanced relative to sheath 902 to expose balloon 914 (or anotherexpandable member), as shown in FIG. 9D. Balloon 914 then is expanded tobring the device (not shown) into apposition with the interior of bodilytissue BT. Balloon 914 may be retained in position for a sufficientperiod of time for the patch to activate and adhere to the bodily tissuewall, e.g., 30 seconds to several minutes. Balloon 914 then is deflatedand delivery system 900 removed.

The multi-layer device of the present invention may be delivered usingany suitable delivery system, such as those described above. Thedelivery system may comprise a sheath, which may or may not besteerable. Advancement of the delivery system and deployment of thedevice may occur under direct visualization, indirect visualization, ora combination thereof. In variations where the delivery system isadvanced using indirect visualization, any suitable visualizationtechnique may be used (i.e., fluoroscopy, ultrasound), and either thedelivery system or the adhesive may include one or more radiographiccomponents to help aid in visualization.

In accordance with the present invention, the multi-layer device may beadvanced to a target location and applied to bodily tissue using atrocar, tweezers, forceps, clamps, or the like and techniques known inthe art.

Multi-layer devices constructed in accordance with the present inventionmay be delivered to any suitable target location of the anatomy. Forexample, one or more devices may be delivered to one or more hollow bodyorgans, such as the esophagus, stomach, intestines, bronchus, trachea,lungs, urethra, ureters, the sinuses, the ears, eyes, or the heart andoptionally exposed to moisture at bodily tissue, e.g., the wall of theorgan. In embodiments configured for use in a heart, the device may beused to treat or seal a patent foramen ovale, a paravalvular leak, theleft auricular appendage, or the like. In other embodiments, theinventive devices may be used to modify the geometry of the leftventricle, and thus reduce functional mitral regurgitation.

Multi-layer devices constructed in accordance with the present inventionmay be delivered to target locations that include wounds resulting frominterventional, minimally-invasive and/or intraoperative surgicalprocedures, diseases, and/or underlying conditions.

In one proposed application, a device of the present invention isadvanced to a target location in the sinuses and applied to bodilytissue within the sinus to treat iatrogenic wounds resulting fromsurgical procedures for treating, for example, sinusitis. The device maybe applied to areas such as, but not limited to, a paranasal sinus,ethmoid sinus, ethmoidotomy channel, and frontal sinus outflow tract. Adevice of the present invention may also be delivered by a deliverysystem, such as the delivery system described above, having anexpandable member (e.g., a balloon, cage, or other expandable structure)or using a sinus insertion device such as a flexible delivery cannula tothe osteomeatal complex, along the maxillary ostium or any sinusinsertion device capable of accessing the maxillary ostium.

A multi-layer device constructed in accordance with the presentinvention provides many advantages for treating wounds, such asiatrogenic wounds resulting from surgical procedures for treatingsinusitis. One advantage is that a therapeutic agent, such as asteroidal anti-inflammatory agent, may be delivered locally with minimalsystemic exposure to significantly improve the outcome of surgery.Another advantage is that the device naturally biodegrades so there isno need for subsequent removal. A further advantage is that the deviceimproves the healing of the mucosal lining so as to reduce healing time,and thus, reduce the likelihood of the formation of adhesions. Yetanother advantage is that the device is configured to seal the mucosalwall, which may prevent adhesions of the opposing surfaces in thesinuses. Another advantage is that the device adheres to the sinus wallof the nasal passageway in a thin layer and therefore does not obstructthe flow of air and liquid; thereby improving the quality of life aftersurgery. Yet a further advantage is that because the device adheres tothe sinus wall, rather than being retained in position by mechanicalforce from, for example, a stent, further damage to the mucosal layer isprevented, which in turn leads to improved quality of life.

In another proposed application, a device of the present invention isadvanced to a target location in the bronchus and applied to bodilytissue at an anastomosis site within the bronchus to treatpost-operative lesions following a surgical procedure, such as lungtransplantation. Bronchial stenosis following lung transplantation issuch a problem, often arising from scar stenosis at the bronchialanastomotic site with or without previous anastomotic dehiscence. Thedevice of the present invention may be delivered to the anastomosis siteusing a suitable delivery system and applied to bodily tissue using theadhesive properties of the device. The device may release therapeuticagent(s) such as cyclosporine or another antiproliferative agents thatpromote healing while the device biodegrades. The device may be appliedto bodily tissue surgically or during an anastomosis procedure.

In a further proposed application, a device of the present invention isadvanced to a target location in the larynx, trachea, carina, or bronchiand applied to bodily tissue at a stenosed area within the larynx,trachea, carina, or bronchi to treat post-operative lesions resultingfrom surgical procedures for treating, for example, airway stenosis,such as post-intubation tracheal stenosis. The device of the presentinvention may be delivered to the affected area using a suitabledelivery system, e.g., in conjunction with balloon dilation opening therestricted passageway. After application, the device may releasetherapeutic agent(s) such as antiproliferative agents and/oranti-inflammatory agents to the affected site to improve the outcome ofthe balloon dilation.

In yet another proposed application, a device of the present inventionis advanced to a target location in a neck in a lobe of the lung andapplied to bodily tissue at the wall of the lobe to treat wounds from,for example, asthma. The device may release therapeutic agent(s) such assteroidal anti-inflammatory agents to the lungs. The device is believedto minimize the systemic exposure to steroids and to improve patientcompliance.

In another proposed application, a device of the present invention isadvanced to a target location in the trachea or bronchi and applied tobodily tissue at a ulcer at the trachea or bronchi to treat lesionsresulting from tumors, for example, squamous cell carcinomas. The devicemay be used to aid in the treatment of bronchial tumor resection orweakened bronchia due to external beam radiation therapy. The device mayrelease therapeutic agent(s) such as chemotherapeutics (e.g.,antiproliferative agents or antibody based therapies), anti-inflammatoryagents, and/or antibiotics to the bodily tissue. The device may bedelivered after open surgery or during an endoscopic procedure such as abronchoscopy.

In yet another proposed application, a device of the present inventionis advanced to a target location in the body and applied to bodilytissue at an internal adhesion or (potential) dermal scar to treatlesions resulting from, for example, invasive surgical procedures. Thedevice may be used in preventing or reducing the size of internaladhesions or dermal scarring. An adhesion is a band of scar tissue thatbinds together two internal body surfaces. Adhesions can causesubsequent health issues such as pain (back and abdominal), infertility,and digestive issues resulting in increased costs and potentialsecondary surgical interventions. The device of the present inventionmay act as a barrier between two body surfaces during the healingprocess; it then biodegrades and provides a space between the twosurfaces. The device also may release therapeutic agent(s) such asanti-inflammatory agents, antiproliferative agents, antibiotics, and/ormitomycin C to promote healing of an adhesion or scar.

In another proposed application, a device of the present invention isadvanced to a target location in or on the body and applied to bodilytissue to promote healing. The device may release therapeutic agent(s)such as antibiotic agents, antimicrobial agents, antifungal agents,growth factors, and/or analgesic agents to promote wound healing. Forexample, a device for treating diabetic ulcers may release an antibioticagent. Advantageously, since the device is biodegradable, it does notneed to be removed before a new dressing is put in place and thereforeprevents interruption of wound healing due to change of dressing.

In a further proposed application, a device of the present invention isadvanced to a target location in or on the body and applied to bodilytissue at a site of pain to treat pain and/or inflammation. For example,the device may be used to treat radicular pain and sciatica of the lowerback or articular pain of the joint. The device may be advanced to atarget location at a joint or a space inside the body using a trocardelivery device. In one embodiment, the device is inserted minimallyinvasively via epidural trocar into the foraminal or interlaminar spaceof the lumbar spine. Preferably, the device is configured to releasetherapeutic agent(s) such as anti-inflammatory agents, analgesic agents,anti-infective agents, and/or anti-proliferative agents. As describedthroughout this disclosure, the device may contain multiple film-layersfor the programmed release of different therapeutic agents withdifferent temporal profiles. For example, acute analgesics such as the-caine derivatives may be delivered immediately and over a duration ofup to the first 8-12 hours, while an anti-inflammatory agent may bedelivered for a much longer period. In another embodiment, the devicemay be applied after an open or minimally invasive surgery (laparoscopicsurgery) to deliver therapeutic agents to improve the outcome of thesurgery. For example, a device with a steroidal anti-inflammatory agentmay be applied after a laparoscopic spinal surgery to reduceinflammation and pain after surgery. In addition, therapeutic agent(s)for promoting wound healing may alleviate the side effects of epiduralsteroid injections such as dural puncture and prevent cerebral spinalfluid leakage.

In yet another proposed application, a device of the present inventionis advanced to a target location in the eye and applied to bodily tissuewithin or on the eye. In one embodiment, the device may be applied tothe posterior segment of the eye via the vitreous or suprachoroidalspace using a cannula, e.g., a 20 to 25 gauge cannula. The device alsomay be applied after vitreoretinal surgery to release a therapeuticagent(s) such as an anti-inflammatory agent over a period of time. Thedevice may biodegrade slowly over time thus obviating the need forsubsequent surgical extraction and may deliver a sustained profile oftherapeutic agent. The adhesive properties of the device allow it to beapplied in contact with and adhering to the macular surface within theeye so as to avoid visual problems associated with an untethered devicein the vitreous.

In another proposed application, a device of the present invention isadvanced to a target location that is a tumor anywhere in or on the bodyand applied to bodily tissue at the tumor as a primary mode of treatmentor in conjunction with surgery or a minimally invasive surgery as amaintenance therapy to prevent tumor re-growth. The device may releasetherapeutic agent(s) such as chemotherapeutics includinganti-proliferative agents to the site of the tumor. Examples for thisapplication include delivering the device using a non-invasive deliverysystem such as a balloon catheter to a tumor of the bladder; deliveringanti-cancer therapeutics to a tumor of the airway using a ballooncatheter; and delivering the device having an anti-cancer agentsurgically to a resected tumor of the pancreas.

In yet another proposed application, a device of the present inventionis advanced to a target location in the heart or in a blood vessel andapplied to bodily tissue at a wall of the heart or vessel to treatwounds from, for example, cardiac disease or surgical procedures fortreating cardiac disease.

Additionally, the device of the present invention may promoteendothelialization by delivery of growth factors. In still otherinstances, one or more devices may be used to attach endothelial cellsto the inside of the lumen to promote healing. In yet another proposedapplication, a device of the present invention may be delivered, e.g.,using a bronchoscope balloon, within a patient's bronchus or trachea todeliver chemotherapy or an anti-cancer drug through the patient'svasculature or tissue.

Device Composition

As described above, first, second, third, fourth, fifth, or morecompositions may be used to form first, second, third, fourth, fifth, ormore film-layers that form a multi-layer device when exposed tomoisture. The compositions and film-layers may comprise fibrinogen,thrombin, therapeutic agent(s), calcium salt, Factor XIII, aprotinin,and/or other additives (e.g., plasticizers, stabilizers, dyes,radio-opacifiers, film-forming agents, and the like) and thecompositions may further include non-aqueous solvent(s) such as ethanol.The compositions of the device may be tailored to achieve variouscharacteristics including a preferred setting time, matrix stiffness,porosity, and degradation rate, depending upon the intended application.The fibrinogen and, if present, thrombin components may be deposited ona surface via spray coating, dip coating, brushing, rolling, spinning,electrospraying, casting, inkjet printing, or the like.

The compositions, and thus the film-layers, described above may furtherinclude an antifibrinolytic agent or antiplasmin agent to prolong thebiodegradation timeline of the device. Examples of antifibrinolyticagents include, but are not limited to, aprotinin, tranexamic acid, andaminocaproic acid.

It is expected that commercially available fibrinogen products may beused to prepare a device in accordance with the present invention. Also,commercially available purified human fibrinogen products preparedwithout any excipients or stabilizers, such as sodium citrate or sodiumchloride, may be used. One commercially available fibrinogen productthat has been used is Part No. PP001S, available from Hyphen Biomed,Neuville-sur-Oise, France, distributed in the United States by AniaraCorporation, Mason, Ohio.

A device in accordance with the present invention may comprise a layerof solid fibrinogen, that may be unsalted, as described above.Fibrinogen-only or fibrinogen plus calcium salt devices are expected tohave different mechanical properties when delivered to tissue comparedto devices that contain thrombin. As explained earlier, however, theaddition and amount of calcium salt may be tailored to obtain specificmechanical properties for a device, as may be suitable for particularapplications.

It is expected that commercially available thrombin also may be used toprepare a device in accordance with the present invention. Initial testsconducted with human thrombin, Part No. AEZ0060, available from HyphenBiomed, Neuville-sur-Oise, France, distributed in the United States byAniara Corporation, Mason, Ohio, have produced satisfactory results. Inaddition, the presence of some excipients in commercial sources ofthrombin have not been observed to effect the mechanical characteristicsof the device.

A device constructed in accordance with the principles of the presentinvention may comprise one or more plasticizers that may increase theflexibility of the device, improving the device integrity and making itless prone to cracking or flaking. Examples of suitable plasticizersinclude, but are not limited to, PEG-6000, PEG-3000, PEG-1500, PEG-400,glycerol, and polyvinyl, phthalate esters (e.g., diethyl phthalate),sebacate esters (e.g., dibutyl sebacate), citrate esters (e.g., triethylcitrate, tributyl citrate), glycerol derivatives (e.g., propyleneglycol, poly(ethylene glycol) which may be about 1 to about 90 weightpercent polyethelene glycol, about 5 to about 75 weight percentpolyethelene glycol, about 5 to about 60 weight percent polyetheleneglycol, about 5 to about 50 weight percent polyethelene glycol, about 5to about 40 weight percent polyethelene glycol, or about 5 to about 30weight percent polyethelene glycol), surfactants, preservatives,combinations thereof, and the like. The amount of plasticizer may varydepending on the intended application as well as the desired flexibilityfor the device, and generally will comprise less than about 50% of theconstituents used to prepare the device.

In other embodiments, a device may comprise one or more radio-opacifiersubstances that allow the device to be imaged fluoroscopically prior to,during, or after implantation. Examples of suitable radio-opacifiersinclude, but are not limited to, materials containing bismuth, barium(e.g., barium sulphate), gold, iodine, platinum, or tantalum, zirconiumoxide and iron oxide. In some embodiments described below, theradio-opacifier may be provided in high concentrations in only discreteareas of the device.

The device of the present invention optionally may incorporate one ormore film-forming agents. Generally, a film-forming agent may assist informing a continuous film-layer during the deposition process, and mayinclude one or more biodegradable polymers, such as, for example,polycarboxylic acid, polyanhydrides (e.g., maleic anhydride polymers),polyorthoesters, poly-amino acids, poly(carbonate), polyethylene oxide,poly(glutarunic acid), polyphosphazenes, polylactic acid, polyglycolicacid, poly(L-lactic acid), poly(D,L,-lactide), poly(lactideacid-co-glycolic acid), 50/50 (DL-lactide-co-glycolide), polydioxanone,polypropylene fumarate, polydepsipeptides, polycaprolactone,(D,L,-lactide-co-caprolactone), poly-caprolactone co-butlacrylate,polyhydroxybutyrate valerate, polycarbonates (e.g., tyrosine-derivedpolycarbonates and arylates), polyiminocarbonates, cyanoacrylate,calcium phosphates, poluglycosaminogycans, polysaccharides (e.g.,hyaluronic acid, cellulose, and hydroxypropylmethyl cellulose), gelatin,starches, dextrans, alginates, proteins, polypeptides, surface erodiblepolymers (e.g., polyhydroxybutyrate, polycaorolactone, polyanhydrides(both crystalline and amorphous), maleic anhydride copolymers, andzinc-calcium phosphate), copolymers thereof, derivatives thereof,mixtures thereof, and the like.

In accordance with another aspect of the present invention, the deviceoptionally may incorporate one or more therapeutic agents intended forlocal or systemic delivery. When a device is delivered into the body,the therapeutic agent may be at least temporarily stored in the device.In some variations, the therapeutic agent may diffuse out of the device.In other variations where the device is biodegradable, the therapeuticagent may be released from the device as the device biodegrades. Theselection of therapeutic agent or agents, the timing of delivery, andthe overall amount of therapeutic agent released from the device may bedetermined by the intended treatment plan, and a specific compositionfor the device may be chosen to achieve this release profile. Invariations where the device includes one or more additional components(e.g., a plasticizer, a film-forming agent, etc.), any of the additionalcomponents may incorporate one or more therapeutic agents.

Examples of suitable therapeutic agents include, but are not limited toanti-inflammatory agents, anti-allergenic agents, anti-bacterial agents,anti-viral agents, anticholinergic agents, antihistamines,antithrombotic agents, anti-scarring agents, antiproliferative agents,antihypertensive agents, anti-restenosis agents, healing promotingagents, vitamins, biological molecules such as proteins, genes, growthfactors, cells and DNA, combinations thereof, and the like.

Examples of suitable anti-allergenic agents that may be suitable for usewith the described methods and devices include, but are not limited to,pemirolast potassium (ALAMAST®, Santen, Inc.) and any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof. Examples of antiproliferative agents include, butare not limited to, actinomycin D, actinomycin IV, actinomycin 11,actinomycin X1, actinomycin C₁, and dactinomycin (COSMEGEN®, Merck &Co., Inc.). Examples of healing promoting agents include, but are notlimited to, sirolimus, everolimus, temsiolimus, and vitamin A.

Examples of antiproliferative agents that may be suitable for use withthe described methods and devices include, but are not limited to,angiopeptin, angiotensin converting enzyme inhibitors such as captopril(CAPOTEN® and CAPOZIDE®, Bristol-Myers Squibb Co.), cilazapril orlisinopril (PRINIVIL® and PRINZIDE®, Merck & Co., Inc.); calcium channelblockers such as nifedipine; colchicines; fibroblast growth factor (FGF)antagonists, fish oil (omega 3-fatty acid); histamine antagonists;lovastatin (MEVACOR®, Merck & Co., Inc.); monoclonal antibodiesincluding, but not limited to, antibodies specific for Platelet-DerivedGrowth Factor (PDGF) receptors; nitroprusside; phosphodiesteraseinhibitors; prostaglandin inhibitors; suramin; serotonin blockers;steroids; thioprotease inhibitors; PDGF antagonists including, but notlimited to, triazolopyrimidine; and nitric oxide, and any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof.

Examples of anti-bacterial agents that may be suitable for use with thedescribed methods and devices include, but are not limited to,aminoglycosides, amphenicols, ansamycins, β-lactams such as penicillins,lincosamides, macrolides, nitrofurans, quinolones, sulfonamides,sulfones, tetracyclines, vancomycin, and any derivatives or combinationsthereof. Examples of penicillins that may be suitable for use with thedescribed methods and devices include, but are not limited to,amdinocillin, amdinocillin pivoxil, amoxicillin, ampicillin, apalcillin,aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillinicacid, benzylpenicillin sodium, carbenicillin, carindacillin,clometocillin, cloxacillin, cyclacillin, dicloxacillin, epicillin,fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin,methicillin sodium, mezlocillin, nafcillin sodium, oxacillin,penamecillin, penethamate hydriodide, penicillin G benethamine,penicillin G benzathine, penicillin G benzhydrylamine, penicillin Gcalcium, penicillin G hydrabamine, penicillin G potassium, penicillin Gprocaine, penicillin N, penicillin 0, penicillin V, penicillin Vbenzathine, penicillin V hydrabamine, penimepicycline, phenethicillinpotassium, piperacillin, pivampicillin, propicillin, quinacillin,sulbenicillin, sultamicillin, talampicillin, temocillin, andticarcillin.

Examples of anti-viral agents suitable for use with the describedmethods and devices include, but are not limited to, acyclovir,famciclovir, valacyclovir, edoxudine, ganciclovir, foscamet, cidovir(vistide), vitrasert, formivirsen, HPMPA(9-(3-hydroxy-2phosphonomethoxypropyl)adenine), PMEA(9-(2-phosphonomethoxyethyl)adenine), HPMPG(9(3-Hydroxy-2-(Phosphonomet-hoxy)propyl)guanine), PMEG(9-[2-(phosphonomethoxy)ethyl]guanine), HPMPC(1-(2-phosphonomethoxy-3-hydroxypropyl)cytosine), ribavirin, EICAR(5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamine), pyrazofurin(3-[beta-D-ribofuranosyl]-4-hydroxypyrazole-5-carboxamine),3-Deazaguanine, GR92938X(1-beta-D-ribofuranosylpyrazole-3,4-dicarboxami-de), LY253963(1,3,4-thiadiazol-2-ylcyanamide), RD3-0028(1,4-dihydro-2,3-Benzodithiin), CL387626(4,4′-bis[4,6-d][3-aminophenylN-,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazin-2-ylamino-biphenyl-2-,2′-disulfonicacid disodium salt), BABIM (Bis[5-Amidino-2-benzimidazoly-I]-methane),NIH351, and combinations thereof.

Anti-inflammatory agents may include steroidal and nonsteroidalanti-inflammatory agents. Examples of suitable steroidalanti-inflammatory agents include, but are not limited to, 21acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, triamcinolonehexacetonide, any of their derivatives, and combinations thereof.

Examples of suitable nonsteroidal anti-inflammatory agents include, butare not limited to, COX inhibitors. These COX inhibitors may includeCOX-1 or COX nonspecific inhibitors such as, for example, salicylic acidderivatives, aspirin, sodium salicylate, choline magnesiumtrisalicylate, salsalate, diflunisal, sulfasalazine and olsalazine;para-aminophenol derivatives such as acetaminophen; indole and indeneacetic acids such as indomethacin and sulindac; heteroaryl acetic acidssuch as tolmetin, dicofenac and ketorolac; arylpropionic acids such asibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin;anthranilic acids (fenamates) such as mefenamic acid and meloxicam;enolic acids such as the oxicams (piroxicam, meloxicam) and alkanonessuch as nabumetone. The COX inhibitors may also include selective COX-2inhibitors such as, for example, diaryl-substituted furanones such asrofecoxib; diaryl-substituted pyrazoles such as celecoxib; indole aceticacids such as etodolac and sulfonanilides such as nimesulide).

Examples of suitable biomolecules include, but are not limited to,peptides, polypeptides and proteins; oligonucleotides; nucleic acidssuch as double or single standard DNA (including naked and eDNA), RNA,antisense nucleic acids such as antisense DNA and RNA, small interferingRNA (siRNA), and ribozymes, genes, carbohydrates. Nucleic acids may beincorporated into one or more vectors (including viral vectors),plasmids, liposomes, or the like.

Examples of suitable proteins include, but are not limited to serca-2protein, monocyte chemoattractant proteins (“MCP-1”) and bonemorphogenic proteins (“BMPs”), such as, for example. BMP-2 (OP-1),BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10,BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. These BMPs may be provided ashomodimers, heterodimers, or combinations thereof. In some variations,molecules capable of inducing an upstream or downstream effect of a BMPmay be provided. This may include, for example, one or more “hedgehog”proteins, or the DNA encoding them. Examples of suitable genes include,but are not limited to survival genes that protect against cell death(e.g., anti-apoptotic Bcl-2 family factors and Akt kinase); SERCA 2gene; and combinations thereof. In some variations, one or moretherapeutic agents may comprise one or more angiogenic factors, such asacidic and basic fibroblast growth factors, vascular endothelial growthfactor, epidermal growth factor, vascular endothelial growth factor,epidermal growth factor, transforming growth factor and,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor, hepatocyte growth factor, and insulinlike growth factor. In some variations, a therapeutic agent may compriseone or more cell cycle inhibitors (e.g., a cathepsin D (CD) inhibitor).Examples of suitable anti-restenosis agents include, but are not limitedto, Rb, nFkB and E2F decoys, thymidine kinase (“TK”), combinationsthereof, and the like.

Examples of suitable small molecules include, but are not limited to,hormones, nucleotides, amino acids, sugars, and lipids and compoundshave a molecular weight of less than 100 kD. Examples of suitable cellsinclude, but are not limited to, stem cells, progenitor cells,endothelial cells, adult cardiomyocytes, smooth muscle cells, sidepopulation (SP) cells, lineage negative (Lin−) cells (e.g., Lin−CD 34−,Lin−CD34+, Lin−cKit+, and the like), mesenchymal stem cells includingmesenchymal stem cells with 5-aza, cord blood cells, cardiac or othertissue derived stem cells, whole bone marrow, bone marrow mononuclearcells, whole bone marrow, bone marrow mononuclear cells, endothelialprogenitor cells, skeletal myoblasts or satellite cells, muscle derivedcells, go cells, endothelial cells, adult cardiomyocytes, fibroblasts,smooth muscle cells, adult cardiac fibro blasts +5-aza, geneticallymodified cells, tissue engineered grafts, MyoD scar fibroblasts, pacingcells, embryonic stem cell clones, embryonic stem cells, fatal orneonatal cells, immunologically masked cells and teratoma derived cells.Cells may be of human origin (autologous or allogenic), of animal origin(xenogenic), or may be genetically engineered. Any of the foregoingdrugs or biologically active molecules may be encapsulated, for example,in microparticles or liposomes, prior to incorporation within thedevice.

Other bioactive agents useful in the present invention include, but arenot limited to, free radical scavengers; nitric oxide donors; rapamycin;methyl rapamycin; everolimus; tacrolimus;40-O-(3-hydroxy)propyl-rapamycin;40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin; tetrazole containingrapamycin analogs; estradiol; clobetasol; idoxifen; tazarotene;alpha-interferon; host cells including, but not limited to prokaryotesand eukaryotes such as, for example, epithelial cells and geneticallyengineered epithelial cells; patient's own platelet rich plasma,dexamethasone; and, any prodrugs, metabolites, analogs, homologues,congeners, derivatives, salts and combinations thereof.

EXAMPLE

Two compositions in accordance with the principles of the presentinvention were prepared using commercially available fibrinogen,thrombin, calcium chloride, PEG, a drug, and ethanol. As will beapparent from observing the table below, Compositions 1 and 2 areidentical except the amount of ethanol is 2.5 ml in Composition 1 and7.5 ml in Composition 2.

Drug Total Fibrin- Throm- Calcium con- ethanol Ambient ogen bin chloridePEG tent content humidity (mg) (U) (mg) (mg) (mg) (ml) (%) Compo- 78 6013.2 30 2 2.5 68 sition 1 Compo- 78 60 13.2 30 2 7.5 68 sition 2

Compositions 1 and 2 were separately poured in a plastic mold having asurface area of 10 cm². Composition 1 was dried using a vacuum tosubstantially eliminate the 2.5 ml of ethanol to form Film-Layer 1.Composition 2 was dried in the same drying conditions as Composition 1to substantially eliminate the 7.5 ml of ethanol to form Film-Layer 2.

The drug release times from Film-Layer 1 and Film-Layer 2 were analyzedin a buffered saline using a reference front high performance liquidchromatography (“RF-HPLC”) system. FIG. 10 is a graph showing thepercentage of drug release from a film-layer over time in minutes.Release time 1000 depicts the percentage of drug release from Film-Layer1 over time and release time 1002 depicts the percentage of drug releasefrom Film-Layer 2 over time. As will be apparent from observing FIG. 10,Film-Layer 2 (initially formed with higher ethanol content) has asignificantly slower drug release profile than Film-Layer 1.

The adhesive properties of 450 mm² samples of Film-Layer 1 andFilm-Layer 2 when applied to collagen films were analyzed using anInstron machine. FIG. 11 is a graph showing the force in Newtons byextension in millimeters of Film-Layer 1 and Film-Layer 2. Adhesive line1100 depicts the force required to extend Film-Layer 1 a distance andadhesive line 1102 depicts the force required to extend Film-Layer 2 adistance. As will be apparent from FIG. 11, Film-Layer 1 (initiallyformed with lower ethanol content) has higher adhesive properties thanFilm-Layer 2.

Surprisingly, although Film-Layer 1 and Film-Layer 2 have significantlydifferent mechanical characteristics, as demonstrated in FIGS. 10 and11, the specimens of each of Film-Layer 1 and Film-Layer 2 appearsubstantially identical when viewed using an optical microscope.

While various illustrative embodiments of the invention are describedabove, it will be apparent to one skilled in the art that variouschanges and modifications may be made therein without departing from theinvention. The appended claims are intended to cover all such changesand modifications that fall within the true spirit and scope of theinvention.

What is claimed is:
 1. A method of manufacturing a device, comprising:forming in vitro a first film-layer from a first composition comprisingsolid fibrinogen and a first amount of non-aqueous solvent by processingthe first composition for a first time interval required tosubstantially eliminate the first amount of non-aqueous solvent, thefirst film-layer exhibiting a first characteristic in vivo; and bondingin vitro a second film-layer to the first film-layer, the secondfilm-layer formed from a second composition comprising solid fibrinogenand a second amount of non-aqueous solvent by processing the secondcomposition for a second time interval required to substantiallyeliminate the second amount of non-aqueous solvent, the secondfilm-layer exhibiting a second characteristic in vivo, wherein the firsttime interval is different from the second time interval and the firstcharacteristic is different from the second characteristic, and thefirst composition is substantially identical to the second composition,except the first amount of non-aqueous solvent is different from thesecond amount of non-aqueous solvent.
 2. The method of claim 1, whereinbonding the second film-layer to the first film-layer comprises bondingthe second film-layer to the first film-layer using an intermediatelayer disposed between the first film-layer and the second film-layer.3. The method of claim 2, wherein the intermediate layer is configuredto dissolve to create a reservoir, pores, void, or channel between thefirst film-layer and the second film-layer.
 4. The method of claim 1,wherein the first film-layer further comprises a first therapeuticagent, wherein the first characteristic is a first release profile forthe first therapeutic agent.
 5. The method of claim 1, wherein thesecond film-layer further comprises a second therapeutic agent, whereinthe second characteristic is a second release profile for the secondtherapeutic agent.
 6. The method of claim 5, wherein the firsttherapeutic agent or the second therapeutic agent or both comprise oneor more anti-inflammatory agents, anti-allergenic agents, anti-bacterialagents, anti-viral agents, anticholinergic agents, antihistamines,antithrombotic agents, anti-scarring agents, antiproliferative agents,antihypertensive agents, anti-restenosis agents, healing promotingagents, vitamins, proteins, genes, growth factors, cells, RNA, or DNA.7. The method of claim 5, wherein the first therapeutic agent isdifferent from the second therapeutic agent.
 8. The method of claim 1,wherein the first characteristic is a first adhesive property of thefirst film-layer and the second characteristic is a second adhesiveproperty of the second film-layer.
 9. The method of claim 1, wherein thefirst characteristic is a first solubility property of the firstfilm-layer and the second characteristic is a second solubility propertyof the second film-layer.
 10. The method of claim 1, wherein the deviceis configured to form a fibrin patch upon exposure to moisture.
 11. Themethod of claim 1, wherein processing the first composition comprisesdrying the first composition.
 12. The method of claim 1, wherein thefirst film-layer or the second film-layer or both further comprisecalcium salt, solid thrombin mixed with the solid fibrinogen, aplasticizer, or a contrast agent that renders the device radiopaque, orany combination thereof.
 13. The method of claim 1, wherein the firstfilm-layer or the second film-layer or both are coated with a protectivelayer.
 14. The method of claim 1, wherein the first film-layer is bondedto the second composition before the second film-layer is formed. 15.The method of claim 1, wherein bonding the second film-layer to thefirst film-layer comprises depositing the second film-layer on the firstfilm-layer.
 16. The method of claim 1, wherein forming the firstfilm-layer comprises forming the first film-layer from the firstcomposition in a mold.
 17. The method of claim 1, wherein the firstcharacteristic is a first surface roughness or texture property of thefirst film-layer comprising surface projections, perforations,microstructures, nanostructures, ridges, dimples, or any combinationthereof, and wherein the second characteristic is a second surfaceroughness or texture property of the second film-layer comprisingsurface projections, perforations, microstructures, nanostructures,ridges, dimples, or any combination thereof.
 18. The method of claim 1,wherein the first composition is processed for a first time interval ina first ambient humidity, and the second composition is processed for asecond time interval in a second ambient humidity, wherein the firstambient humidity is different from the second ambient humidity.